In Vitro Activity and Microbiological Efficacy of Gepotidacin from a Phase 2, Randomized, Multicenter, Dose-Ranging Study in Patients with Acute Bacterial Skin and Skin Structure Infections

Nicole E Scangarella-Oman, Karen A Ingraham, Courtney A Tiffany, Lynn Tomsho, Stephanie F Van Horn, David N Mayhew, Caroline R Perry, Theresa C Ashton, Etienne F Dumont, Jianzhong Huang, James R Brown, Linda A Miller, Nicole E Scangarella-Oman, Karen A Ingraham, Courtney A Tiffany, Lynn Tomsho, Stephanie F Van Horn, David N Mayhew, Caroline R Perry, Theresa C Ashton, Etienne F Dumont, Jianzhong Huang, James R Brown, Linda A Miller

Abstract

A phase 2 study of gepotidacin demonstrated the safety and efficacy of 3 gepotidacin doses (750 mg every 12 h [q12h], 1,000 mg q12h, and 1,000 mg every 8 h [q8h]) in hospitalized patients with suspected/confirmed Gram-positive acute bacterial skin and skin structure infections (ABSSSIs). Evaluating microbiology outcomes and responses were secondary endpoints. Pretreatment isolates recovered from infected lesions underwent susceptibility testing per Clinical and Laboratory Standards Institute guidelines. Staphylococcus aureus accounted for 78/102 (76%) of Gram-positive isolates; 54/78 (69%) were methicillin-resistant S. aureus (MRSA), and 24/78 (31%) were methicillin-susceptible S. aureus (MSSA). Posttherapy microbiological success (culture-confirmed eradication of the pretreatment pathogen or presumed eradication based on a clinical outcome of success) for S. aureus was 90% for the gepotidacin 750-mg q12h group, 89% for the 1,000-mg q12h, and 73% in the 1000-mg q8h group. For 78 S. aureus isolates obtained from pretreatment lesions, gepotidacin MIC50/MIC90 values were 0.25/0.5 μg/ml against both MRSA and MSSA. Isolates recovered from the few patients with posttreatment cultures showed no significant reduction in gepotidacin susceptibility (≥4-fold MIC increase) between pretreatment and posttreatment isolates. Two of the 78 S. aureus isolates from pretreatment lesions had elevated gepotidacin MICs and had mutations known to occur in quinolone-resistant S. aureus (GyrA S84L, ParC S80Y, and ParE D422E) or to confer elevated MICs to novel bacterial topoisomerase inhibitors (GyrA D83N, both isolates; ParC V67A, one isolate). This first report of microbiological outcomes and responses of gepotidacin in patients with ABSSSIs supports further evaluation of gepotidacin as a novel first-in-class antibacterial agent. (This study has been registered at ClinicalTrials.gov under identifier NCT02045797.).

Keywords: ABSSSI; GSK2140944; MRSA; MSSA; S. aureus; antibacterial agent; gepotidacin; skin infection.

Copyright © 2020 Scangarella-Oman et al.

Figures

FIG 1
FIG 1
Frequency distribution of gepotidacin MICs against S. aureus isolates from pretreatment lesion samples (mMITT population). GEP, gepotidacin; mMITT, modified microbiological intent-to-treat; MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus.
FIG 2
FIG 2
Phylogenetic maximum likelihood tree constructed from a ClustalW alignment of a concatenated set of gene sequences from the 12 isolates in the present study and another 2 reference genomes from GenBank. Nodes of branch points marked with an asterisk were supported in more than 80% of 1,000 bootstrap replications. The scale bar indicates the number of substitutions per position for a unit branch length. Gepotidacin MICs and strain types from MLST analysis appear for each of the sequenced isolates. Gep, gepotidacin; MLST, multilocus sequence typing.

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